Pharmaceuticals are commonly administered parenterally in isotonic solutions. However, this dosage form is not always well suited for all drugs or prolonged drug therapies. To overcome these and other short comings of this dosage form several new injectable dosage formulations have recently been developed.
The most notable recent development has been the use of bioerodible or bioabsorbable polymers in injectable dosage formulations. Several publications describe these new injectable dosage formulations such as U.S. Pat. No. 3,982,537 and U.S. Pat. No. 4,054,138 issued to Bucalo, U.S. Pat. No. 4,938,763 issued to Dunn et al. and "Biodegradable block copolymer matrices for long-acting contraceptives with constant release" J. Contr. Rel. 32. (1992) 3-14 by Z. W. Gu et al. Each of these publications presents a different formulation that may one day replace conventional parenteral formulations.
Bucalo describes the use of low melting hydrogenated vegetable oils and fats as injectable in-situ implants or injectable microspheres. The implants are formed from vegetable oil or fat that is melted and mixed with a drug. The mixture is then either injected into the patient where the mixture will solidify to form an in-situ implant, or formed into microspheres that are injected. Although this formulation may work for some drugs, the heat necessary to form the liquid mixture of oil or fat and drug will in many cases inactivate or modify the drug being administered.
Dunn et al. describes a different biodegradable in-situ implant that does not require the formulation to be heated. Dunn proposes the use of a liquid polymer carrier that solidifies in-situ by crosslinking or precipitation due to solvent dissipation. Although, Dunn avoids the heat inactivation problems inherent with Bucalo's implants, Dunn's formulations also have significant short comings. The polymer system described by Dunn et al. is based on DL-lactide or L-lactide and .epsilon.-caprolactone copolymers. The copolymers are used as prepolymers, which will be derivatized and crosslinked in-situ or dissolved in a solvent. Unfortunately, the crosslinking process requires formulation and mixing of the injectable immediately before administration, which is generally not practical. The solvent based implants, although easier to administer, cannot readily be used because the solvents necessary to dissolve the .epsilon.-caprolactone based copolymers that Dunn describe are toxic.
Gu and coworkers describes a formulation containing hard microspheres of a triblock copolymer, namely poly(.epsilon.-caprolactone-b-D,L-lactide-b-glycolide) for the controlled release of contraceptives. The microspheres that Gu describe are designed to be injected, thereby avoiding the need to surgically implant a solid dosage. Unfortunately, the kinetics of the pharmaceutical release from these microspheres are complicated by the different release mechanisms of the individual blocks of the triblock copolymer. Although the complicated release mechanism is not an insurmountable obstacle to the use of Gu's microspheres, it makes formulation of sustained release injectables quite difficult.
Thus it would be a significant contribution to the art to provide an injectable dosage form that is easy to administer and provides sustained or extended drug release.